Although the cardiovascular benefit of statin medications is well established, statin-associated muscle symptoms (SAMS) are the most common adverse effect observed with this medication class.1 Often, the occurrence of these side effects or patient fear of side effects result in discontinuation of statin therapy, which has been associated with worsened cardiovascular outcomes.2 SAMS encompasses myalgia, myopathy, and rhabdomyolysis related to statin therapy.
Prior to discontinuing statin therapy, it is important to assess if patient-reported symptoms are truly related to statin therapy. The Statin-Associated Muscle Symptom Clinical Index is a tool that can be used to determine the likelihood that these symptoms correlate with statin usage.3 It incorporates the location of symptoms, onset, symptom recurrence, or symptom improvement after dechallenge or rechallenge to produce an index score rating symptoms from unlikely to probably statin-associated.
When a patient presents with possible SAMS, it is important to assess for potential drug interactions that may have increased this risk. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4. Inhibitors of this pathway, such as amiodarone, cyclosporine, azole antifungals, and protease inhibitors, can elevate statin concentrations, thereby increasing the risk of SAMS. Rosuvastatin, fluvastatin, and pitavastatin primarily rely on CYP2C9 for metabolism, and their interaction with inhibitors of this enzyme, such as amiodarone, fluvoxamine, and azole antifungals, can similarly increase the risk of SAMS.4 These do not encompass all potential interactions, and the possibility of drug interactions should be assessed when there is a potential for SAMS.
A 2-week dechallenge followed by statin reintroduction may assist with determining if symptoms are associated with statin therapy. Additionally, hydrophilic statins, such as rosuvastatin and pravastatin, have been associated with less muscle symptoms and can be trialed as an alternative to the patient’s current statin therapy. Intermittent statin dosing has been studied with rosuvastatin due to its long half-life, and every-other-day dosing has been found to be tolerated in prior statin-intolerant patients and lower LDL-C.5
The majority of patients with SAMS have a partial intolerance to statins and may be able to tolerate alternative statins, reduced dosing, or intermittent dosing. Complete statin intolerance, defined as an inability to tolerate statins at any lipid lowering doses, is relatively rare and occurs in fewer than 5% of patients.6 In these cases, nonstatin therapies are usually required, such as ezetimibe, PCSK9 inhibitors, bempedoic acid, or inclisiran.
Ezetimibe is a selective cholesterol absorption inhibitor that works at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-like1. Inhibition of this transporter leads to a decrease in cholesterol delivery to the liver and an increase in cholesterol clearance.7 Ezetimibe, often considered a second-line treatment option for hypercholesterolemia, yields an 18% reduction in LDL-C when used as monotherapy.8 Ezetimibe is generally well tolerated and has minimal drug-drug interactions due to its lack of influence on or susceptibility to CYP450 enzymes.7 The IMPROVE-IT trial demonstrated a significant reduction in cardiovascular events with the addition of ezetimibe to a statin compared to statin monotherapy. There was no difference in rhabdomyolysis or myopathy between the 2 groups.9
Bempedoic acid exerts its cholesterollowering effect by inhibiting ATP citrate lyase, an enzyme preceding HMG-CoA reductase in hepatocytes. Bempedoic acid is a prodrug and requires activation by very-long-chain acyl-CoA synthetase A, predominantly found in the liver and kidney. The lack of expression of the activating enzyme in skeletal muscle mitigates the risk of myotoxicities associated with other lipid-lowering agents.7 Bempedoic acid demonstrated a significant reduction in the incidence of major adverse cardiovascular events among patients intolerant to statins in the CLEAR Outcomes trial. Approximately 23% of patients in both the intervention and placebo groups were on some dose of a statin, with similar rates of mylagia observed between the groups (5.6% vs 6.8%, respectively). Adverse events noted in the trial results included a reduction in uric acid and creatinine excretion, increase in hepatic enzyme levels, and increased incidence of gout and cholelithiasis10 Tendon rupture has been observed with bempedoic acid, so this agent should be avoided in patients with a history of tendon rupture or other tendon disorders. CLEAR Serenity specifically evaluated bempedoic acid in patients with statin intolerance and demonstrated a significant reduction in LDL with myalgia occurring in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively.11 The 2024 American Diabetes Association Standards of Care offer a category A recommendation for the use of bempedoic acid in primary prevention to reduce cardiovascular event rates in patients with diabetes who cannot tolerate statins.12
The monoclonal antibodies evolocumab and alirocumab target proprotein convertase subtilisin/kexin type 9 (PCSK9) to prevent degradation of LDL receptors. This leads to enhanced receptor recycling and increased uptake of circulating LDL. These medications may be used as monotherapy or in conjunction with other agents for the management of homozygous familial hypercholesterolemia or secondary prevention of cardiovascular events.7 The PCSK9 inhibitors are administered via subcutaneous injection every 2 or 4 weeks, resulting in a reduction in LDL-C levels ranging from 45% to 64%.8 The FOURIER and ODYSSEY OUTCOMES trials demonstrated a significant decrease in cardiovascular event risk associated with evolocumab and alirocumab, respectively, when added to maximum tolerated statin therapy. Evolocumab and alirocumab were overall well tolerated in these trials, with mild injection-site reactions occurring more frequently in the treatment group.13-14 In the GAUSS-2 trial, the comparison between evolocumab and ezetimibe in statin-intolerant patients revealed a lower incidence of myalgia with evolocumab compared to ezetimibe (8% vs 18%). Discontinuation rates due to musculoskeletal side effects were similar in both groups.15 Similarly, in the ODYSSEY ALTERNATIVE trial, alirocumab was compared to ezetimibe in statin-intolerant patients, revealing a trend toward lower rates of discontinuations due to treatment-emergent adverse events and musculoskeletal side effects in the alirocumab treatment arm.16
Lastly, the newest nonstatin agent, inclisiran, is a small interfering RNA medication that inhibits the production of PCSK9 from the liver, thus reducing LDL. Inclisiran is administered in office by a health care professional twice yearly following an initial dose and second dose 3 months later. It can be considered in patients who have not tolerated evolocumab or alirocumab, patients who are unable to self-inject, or patients with poor adherence to medications. Inclisiran administration can often be aligned with clinic appointments to promote adherence. The ORION-10 and ORION-11 trials showed a significant reduction in LDL cholesterol by about 50% when added to maximal tolerated statin therapy; the primary adverse effect observed was injection-site reactions.17 When the group of patients with statin intolerance were evaluated, inclisiran lowered LDL by an average of 44.5% in those not receiving statin therapy. Rates of adverse effects were similar between the inclisiran group and placebo group.18 The VictORION trial series are currently ongoing and will evaluate the impact of inclisiran on cardiovascular outcomes for primary and secondary prevention in patients receiving maximally tolerated statin therapy.
Statin agents remain the “gold standard” for LDL lowering and in primary and secondary prevention of cardiovascular disease. Complete statin intolerance is uncommon; however, some patients are unable to tolerate these agents primarily due to muscle-related adverse effects. Health care professionals should assess if these reported symptoms are likely related to the statin therapy prior to discontinuation and may try different strategies to enhance statin tolerance. If the patient has a true statin intolerance, there are several nonstatin agents that may be considered depending on the amount of LDL-C reduction that is indicated and other factors, such as ability to self-inject and medication cost. Health care professionals should consider prior therapies and lifestyle factors to develop a patient-specific therapy plan for the prevention of cardiovascular disease.
Meissane Lee, PharmD, BCACP, is with Houston Methodist Willowbrook Hospital in Houston, TX. Ana Safri, PharmD, MBA, BCACP, is with Boston Medical Center in Boston, MA.
The authors declare having no professional or financial association or interest in an entity, product, or service related to the content or development of this article.
The authors declare having received no specific grant from a funding agency in the public, commercial, or not-for-profit sectors related to the content or development of this article.
Meissane Lee https://orcid.org/0000-0002-7238-7318
Stroes ES, Thompson PD, Corsini A, et al; European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-1022.
Heeschen C, Hamm CW, Laufs U, et al; Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002;105(12):1446-1452.
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Cheeley MK, Saseen JJ, Agarwala A, et al. NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient. J Clin Lipidol. 2022;16(4):361-375.
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Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardio. 2022;80(14):1366-1418.
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.
Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388(15):1353-1364.
Laufs U, Banach M, Mancini GBJ. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc. 2019;8(7):e011662. doi:10.1161/JAHA.118.011662
American Diabetes Association Professional Practice Committee. 10. Cardiovascular disease and risk management: standards of care in diabetes—2024. Diabetes Care. 2024;47(supple 1):S179-S218.
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722.
Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097-2107.
Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541-2548.
Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758-769.
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